Heterogeneous presentation in A3243G mutation in the mitochondrial tRNALeu(UUR) gene

Aims-To clarify the phenotype-genotype relation associated with the A3243G mitochondrial DNA mutation. Methods-Five unrelated probands harbouring the A3243G mutation but presenting different clinical phenotype were analysed. Probands include Leigh syndrome (LS3243), mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS(3243)), progressive external ophthalmoplegia (PEO3243), and mitochondrial diabetes mellitus (MDM3243). Extensive clinical, histological, biochemical, and molecular generic studies were performed on five families. Results-All patients showed ragged red fibres (RRF), and focal cytochrome c oxidase (COX) deficiency except for the patient with MDM3243. The mutation load was highest in the proband with LS3243 (>90%), who also presented the highest proportion of RRF (68%) and COX negative fibres (10%), and severe complex I plus IV deficiency. These proportions were lower in the probands with PEO3243 and with MDM3243. Conclusion-The most severe clinical phenotype, LS3243, was associated with the highest proportion of the A3243G mutation as well as the most prominent histological and biochemical abnormalities.